Most cellular ATP is synthesized in the mitochondria through the process of oxidative phosphorylation. The mitochondrial electron transport or respiratory chain is a series of enzyme complexes in the mitochondrial membrane that is responsible for the transport of electrons from NADH to oxygen and the coupling of this oxidation to the synthesis of ATP (oxidative phosphorylation). ATP then provides the primary source of energy for driving a cell's many energy-requiring reactions. The activities of the enzymes of the mammalian oxidative phosphorylation system vary greatly in response to a number of physiological conditions, including cell proliferation, hormonal stimulation, development, and differentiation.
ATP synthase (F.sub.1 F.sub.0 ATPase) is the enzyme complex which serves as a reversible coupling device that interconverts the energies of an electrochemical proton gradient across the mitochondrial membrane into either the synthesis or hydrolysis of ATP. This gradient is produced by other enzymes of the respiratory chain in the course of electron transport from NADH to oxygen. When the cell's energy demands are high, electron transport from NADH to oxygen generates an electrochemical gradient across the mitochondrial membrane. Proton translocation from the outer to the inner side of the membrane drives the synthesis of ATP. Under conditions of low energy requirements, and when there is an excess of ATP, this electrochemical gradient is reversed and ATP synthase hydrolyzes ATP. The energy of ATP hydrolysis is used to pump protons out of the mitochondrial matrix.
ATP synthase is a complex composed of two structurally and functionally distinct sectors termed F.sub.1 and F.sub.0 The F.sub.1 sector is bound at the membrane surface and functions as the catalytic portion which synthesizes or hydrolyzes ATP. The F.sub.0 sector is the transmembrane proton carrier or pump and spans the mitochondrial membrane. Subunits .alpha., .beta., .gamma., .delta., .epsilon., and an ATPase inhibitor protein, IF.sub.1, comprise the Dglobular catalytic F.sub.1 portion of the complex. Subunits a, b, c, d, e, f, g, F6, OSCP, and A6L comprise the proton-translocating, membrane spanning F.sub.0 portion of the complex. A stalk portion of 40-50 angstroms in length connects the F.sub.1 and F.sub.0 portions together and serves to transfer electrochemical energy between them. Subunits from both portions of the ATP synthase complex contribute to the stalk. They are the.gamma., .delta., and .epsilon. subunits from F.sub.1, and F6, OSCP, b, and d subunits from F.sub.0. The mammalian ATP synthase complex comprises at least 16 subunits encoded by nuclear DNA and 2 subunits (subunit A6L and .alpha.) encoded by mitochondrial DNA (Belogrudov, G. I., et al. (1996) J. Biol. Chem. 271:20340-20345.)
A mutation in the ATP synthase subunit A6L gene has been genetically linked to maternally inherited genetic diseases including neurological muscle weakness and cases of subacute necrotizing encephalopathy. To investigate the biochemical effects of an ATP synthase subunit A6L leu156.fwdarw.arg mutation on F.sub.1 F.sub.0 -ATP synthase, a leu207.fwdarw.arg mutation was constructed in F.sub.1 F.sub.0 -ATP synthase from E. coli. Characterization of the mutated enzyme revealed that the mutation abolished detectable ATP synthesis via oxidative phosphorylation. The leu 207.fwdarw.arg mutation results in a structural alteration that blocks proton translocation through F.sub.1 F.sub.0 -ATP synthase (Hartzog P. E. and Cain B. D. (1993) J. Biol. Chem. 268:12250-12252.)
The discovery of a new ATP synthase subunit homolog and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of neurodegenerative disorders, myopathies, cancer, and immune disorders.